Intractable pain has significant adverse effects on quality of life measures, and none of the available treatments can completely reverse these symptoms. Furthermore, currently available pain therapies are often associated with serious side effects. Recent studies indicate that T-type calcium channels (T-channels) function as signal amplifiers in acute and chronic nociceptive processing. We demonstrated that CaV3.2 T- currents are selectively up-regulated in a subpopulation of nociceptive dorsal root ganglion (DRG) neurons of rats with early painful streptozocin-induced peripheral diabetic neuropathy (PDN). Also, selective in vivo silencing of CaV3.2 channels in DRG neurons completely reversed hyperalgesia in rats with PDN, while having a smaller effect on nociception in healthy rats. Importantly, mice lacking CaV3.2 channels did not develop early hyperalgesia of PDN. These results for the first time strongly indicate the potential value of T-channels as a target for the treatment of painful PDN. Biophysical, pharmacological and modeling studies will be performed with DRG neurons from diabetic rats in vitro, as well as pain studies with whole animals. It is hypothesized that an increase in the availability of T-channels in DRG neurons will enhance the ability of voltage-dependent blockers to interact with these channels and thus reverse the increased cellular excitability of nociceptors and more potently affect pain thresholds in diabetic than healthy animals. Thus, lowering the dosage of drugs in vivo may greatly decrease risk of unwanted side effects. It is anticipated that this approach may ultimately lead to better and safer therapies for altered pain sensation in patients with diabetes. It is hoped that this approach may greatly decrease need for the use of narcotics and potential for drug abuse in patient populations suffering from intractable neuropathic pain. PUBLIC HEALTH RELEVANCE: Intractable pain has significant adverse effects on quality of life measures, and currently available treatments can not completely reverse these symptoms and are often associated with serious side effects. This proposed research will study the role of voltage-dependent blockers of T-type calcium channels in reversing enhanced excitability of sensory neurons associated with painful diabetic neuropathy. We anticipate that this approach will ultimately lead to better treatments for intractable neuropathic pain in patients with diabetes. It is hoped that this approach may greatly decrease need for the use of narcotics and potential for drug abuse in patient populations suffering from intractable neuropathic pain.